tbuckley/cabot-search huggingface dataset:
BIOM-26. GENOME-WIDE SOMATIC COPY NUMBER ALTERATION SIGNATURES HAVE PROGNOSTIC IMPLICATIONS FOR ADULT ASTROCYTIC GLIOMA
Authors: Nicholas Nuechterlein, Beibin Li, Linda Shapiro, Patrick Cimino, Eric Holland
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The molecular landscape of adult diffuse glioma has been extensively characterized by gene expression and DNA methylation profiling, but less attention has been paid to somatic copy number alteration (SCNA) data. This study aimed to give a rigorous, survival-focused analysis of glioma genome-wide SCNA data that builds on our previous work. METHODS Detailed survival analyses were conducted on the substructure of UMAP projections of all TCGA glioma (Nf1092), exclusively astrocytic glioma (Nf914), and exclusively IDH-wildtype glioma (Nf528). Results were validated with data from the Glioma Longitudinal Analysis Consortium (GLASS) (Nf224). Clinical factors such as age and MGMT methylation were tested in multivariate survival analyses. RESULTS A UMAP projection of TCGA glioma SCNA data generated three distinct clusters composed of entirely oligodendroglioma, predominantly IDH-mutant astrocytoma (C-IDHmut-astro), and predominantly IDH-wildtype glioma (C-IDHwt), respectively. For astrocytic tumors, cluster assignment was independently prognostic of IDH status (p&amp;lt; 0.001): TCGA IDH-mutant astrocytomas that clustered in C-IDHwt had poorer outcomes than their counterparts (p&amp;lt; 0.04) and IDH-wildtype tumors that clustered in C-IDHmut-astro fared better than those that did not (p&amp;lt; 0.01). The distribution of GLASS astrocytic tumors, which is skewed for better survival, supported our results in IDH-wildtype glioblastoma (p&amp;lt; 0.001, Fisher’s). Among four distinct subclusters of TCGA IDH-wildtype glioblastomas, the largest was significantly or marginally significantly negatively prognostic compared to each other cluster (p=0.048, p=0.059, p=0.027) and their combination (p=0.002). In the GLASS dataset, inclusion in the largest subcluster was also prognostic (p=0.013) and similar trends were observed between individual clusters (p=0.21, p=0.036, p=0.083). Furthermore, membership to the largest cluster was independently prognostic of MGMT methylation status and several published IDH-wildtype glioblastoma subtypes in the TCGA. CONCLUSIONS Unsupervised learning of genome-wide SCNA has prognostic implications for astrocytic glioma. SCNA cluster membership is independently prognostic of MGMT methylation status.
NIMG-05. DYNAMIC SUSCEPTIBILITY CONTRAST MRI IN THE EVALUATION OF BRAIN METASTASES: CURRENT PRACTICE REVIEW AND RATIONALE FOR STUDY OF BASELINE PERFUSION IMAGING PRIOR TO STEREOTACTIC RADIOSURGERY (STARBEAM-X)
Authors: Caroline Dobeson, Matthew Birkbeck, Priya Bhatnagar, Julie Hall, Rachel Pearson, Serena West, Philip English, David Butteriss, Joanne Lewis
Journal: Neuro-Oncology (2022)

Abstract Stereotactic radiosurgery (SRS) is an established focal treatment for brain metastases with high local control rates. An important side-effect of SRS is the development of radionecrosis. On conventional MR imaging, radionecrosis and tumour progression often have similar appearances, but have contrasting management approaches. Perfusion MR imaging is often used in the post-treatment setting in order to help distinguish between the two, but image interpretation can be fraught with challenges.Perfusion MR plays an established role in the baseline and post-treatment evaluation of primary brain tumours and a number of studies have concentrated on the value of perfusion imaging in brain metastases. Of the parameters generated, relative cerebral blood volume is the most widely used variable in terms of its clinical value in differentiating between radionecrosis and tumour progression.Although it has been suggested that the rCBV tends to be elevated in active metastatic disease following treatment with radiosurgery, but not with treatment-related changes, the literature available on interpretation of the ratios provided in the context of defining tumour progression is not consistent.We provide an overview of the role perfusion MRI plays in the assessment of brain metastases and introduces the rationale for the STARBEAM-X study (Study of assessment of radionecrosis in brain metastases using MR perfusion extra imaging), which will prospectively evaluate baseline perfusion imaging in brain metastases. We present here the results of the first three patients recruited to the feasibility phase of this study. We hope this study will allow insight into the vascular appearance of metastases from different primary sites, and aid in the interpretation of post-treatment perfusion imaging.
CTNI-17. A MULTI-INSTITUTIONAL RANDOMIZED CLINICAL TRIAL COMPARING ASSAY - GUIDED CHEMOTHERAPY WITH PHYSICIAN-CHOICE TREATMENT FOR RECURRENT HIGH-GRADE GLIOMA (NCT03632135)
Authors: Tulika Ranjan, Soma Sengupta, Michael Glantz, Richard Green, Alexander Yu, Dawit Aregawi, Rekha Chaudary, Ricky Chen, Mario Zuccarello, Christine Lu-Emerson, Hugh Moulding, Neil Belman, Jon Glass, Aaron Mammoser, Mark Anderson, Nicholas Marko, Jason Schroeder, Steven Jubelirer, Frances Chow, Anthony Alberico, Candace Howard, Seth Lirette, Krista Denning, Jagan Valluri, Pier Paolo Claudio
Journal: Neuro-Oncology (2022)

Abstract The presence of therapy-resistant cancer stem cells (CSCs) in recurrent high-grade glioma (HGG) patients contributes to poor clinical outcomes. The ChemoID functional anti-cancer assay targets cancer stem cells along with the bulk of the tumor cells. This trial aims to determine if ChemoID assay-guided treatment improves survival rates for recurrent HGG patients compared to the empirically physician-selected treatment. Patients with grade-III/IV recurrent glioma who failed standard of care (SOC) therapy were randomized (1:1) between two intervention groups. They received one of fourteen mono or combination chemotherapies based on the ChemoID assay or physician choice. The study met the primary outcome in the first interim analysis of 50 patients as per protocol. The ChemoID group had an improved survival rate (vs physician-choice). Median OS (mOS) was 12.5 months in the ChemoID group (95% CI, 10.2-14.7) vs 9 months in the physician-choice (95% CI, 4.2-13.8; log-rank P = .010). Mortality risk was lower in the ChemoID group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression-free survival was 10.1 months in the ChemoID group vs 3.5 months in the physician choice (95% CI, 4.8-15.4 vs 1.9-5.1; log-rank &amp;lt; 0.001). Risk of progression was lower in the ChemoID group (HR = 0.25; 95% CI, 0.14-0.44; P &amp;lt; 0.001). The intention to treat (ITT) analysis of 78 patients showed substantially improved OS. The ChemoID group had a statistically significant longer median survival of 4.5 months. mOS was 12.0 months in the ChemoID group (95% CI, 10.8-13.2) vs 7.5 in the physician-choice group (95% CI, 3.5-11.5; log-rank P = .009). The ChemoID group had a decreased mortality risk (HR = 0.52; 95% CI, 0.24-0.81; P = .008). Compared with the physician-choice, the ChemoID group had a significantly longer OS in the ITT population. Our findings support that screening standard cytotoxic chemotherapies with a patient-specific anti-cancer assay improves survival outcomes in recurrent HGG patients.
TMET-35. ONE CARBON AND NUCLEOTIDE METABOLISM ARE NOVEL TARGETS IN PEDIATRIC BRAINSTEM TUMORS
Authors: Ian Mersich, Angelo D'Alessandro, Pankaj Desai, Larry Sallans, Biplab Dasgupta
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) are inoperable tumors of the brainstem with no cure. The median survival of children with DIPG is less than 2 years and 5-year overall survival is only 1%. Genomic studies have identified recurrent mutations in histone H3, ACVR and TP53 genes in DIPG. However, there are still no breakthrough drug targets for DIPG. To better understand the disease biology and find new drug targets for DIPG, we recently performed joint pathway analysis of DIPG metabolites (untargeted metabolomics) and differentially expressed genes (RNAseq) relative to normal human neural stem cells. We discovered that specific enzymes of the de novo purine biosynthesis pathway (DNPB), serine synthesis and the associated and one-carbon (1C) metabolism are highly active and the most upregulated in DIPG tumors and cell lines. Gain and loss of function experiments as well as pharmacological studies indicated a mechanistic link between DIPG mutations and DNPB pathway and the dependence of DIPG cells on specific DNPB and 1C metabolism enzymes for in vitro and in vivo growth. The 1C pathway is crucial for rapidly proliferating malignant cells as it senses and regulates cellular nutrient status by allocating and cycling 1C-groups between different acceptor compounds. It controls synthesis of nucleotides, amino acids, glycogen and phosphoglyceride precursors, S-adenosylmethionine (SAM), glutathione and NADPH. Thus, besides dispensing carbon atoms it also regulates cellular epigenetic and redox status. An important carbon donor is serine which is synthesized from glucose at 3-phosphoglycerate step in glycolysis. Untargeted as well as carbon and nitrogen tracing experiments indicated large folate pools in DIPG cells that can serve as a buffer to potentially blunt antifolate therapy. Experiments are underway to understand the importance of the folate cycle in DIPG and design novel and translatable combination therapies for DIPG.
TMIC-80. SPATIOTEMPORAL GENOMICS OF HUMAN MEDULLOBLASTOMA WITHIN SUBGROUPS
Authors: Hailong Liu, Xiaoguang Qiu, Tao Jiang
Journal: Neuro-Oncology (2022)

Abstract Whereas evidences of single-cell studies have suggested the cellular diversity of medulloblastoma, the most common malignant brain tumor in childhood, the understanding of spatial status for specific cell populations and gene modules remains rudimentary. Herein, we comprehensively analyze single-nucleus RNA expression, chromatin accessibility and spatial transcriptomic profiling from 52 human medulloblastomas spanning four molecular subgroups, complemented with the bulk whole genome and RNA sequencing data across 300 samples. We comprehensively interrogated the composition of medulloblastoma microenvironment and spatially described the developmental trajectory from progenitor-like to differentiated malignant cells. Furthermore, distinct heterogeneity within molecular subgroups leads to the identification of twelve subtypes of medulloblastoma, which unfortunately lacks the cellular biology. By deciphering the copy number variation and transcriptional programs at single-cell resolution, we in-depth characterized medulloblastoma and mapped the activity of gene expression and transcription factor binding according to individual subtype. The WNT-β, SHH-γ, Group 3-β and Group 4-γ were observed in early differentiation stage. Harmony alignment revealed subtype-dependent modules recapitulated the neurodevelopmental gene enrichment, strongly correlating to clinical outcomes. Collectively, our findings provide spatiotemporally resolved insights into transcriptome and epigenome of twelve-subtype medulloblastoma allowing further refinement regarding clinical risk stratification strategies.
CTIM-13. LOCAL ADOPTIVE CELLULAR IMMUNOTHERAPY WITH CYTOKINE-INDUCED KILLER (CIK) CELLS FOR HIGH GRADE GLIOMAS: A PILOT STUDY WITH LONG-TERM FOLLOW-UP AND POTENTIAL FACTORS FOR SURVIVAL BENEFITS
Authors: Hao Duan, Yukun Chen, Zhenqiang He, Ke Sai, Yonggao Mou
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Immunotherapy is emerging as a promising approach for the treatment of high grade gliomas (HGGs). We reported the long-term follow-up of 6 HGG patients treated by local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor cavity following operation. Meanwhile, Gene expression profiles and immune microenvironments of tumors were further compared between the long-term and short -term survivors. METHODS Clinicopathological characteristics and outcomes of patients were reviewed and updated. Gene expression profiles, expressions of cytokines and infiltrations of immune cells in tumors were investigated by RNA sequencing, an electrochemiluminescence assay and immunohistochemistry staining, respectively RESULTS Fever and symptoms of encephaledema occurred in 5 patients after local administration of CIK cells, and could be efficiently relieved by mannitol and dexamethasone. Four patients died from progressive disease during follow-up, and their overall survival ranged from 6 to 26 months. Remarkably, 2 patients have survived more than 200 months without evidence of recurrence. Comparing with the tumors of the short-term survivors, 353 genes which were highly associated with tumor microenvironment immune were differentially expressed (false discovery rate (FDR) &amp;lt; 0.05 and log2 fold change (FC) ≥ 1) in the tumor of the long-term survivor. Higher expressions of cytokines, especially IL-8 and IL-10, were observed in the tumor of the long-term survivor, while the infiltrations of M2 polarized macrophages were significantly higher in the tumors of short-term survivors. CONCLUSION Long-term survival of HGG patients could achieve after local administration of CIK cells into tumor cavity postoperatively. High expressions of cytokines and low infiltrations of M2 polarized macrophages in the tumors potentially benefited the CIK cell therapy.
CTNI-56. A MULTI-INSTITUTIONAL RETROSPECTIVE SERIES OF ADULT-ONSET MEDULLOBLASTOMA
Authors: Alipi Bonm, Michael Rutenberg, Kate Therkelsen, Amber Ruiz, Tresa McGranahan, Patrick Cimino, Seema Nagpal, Lynne Taylor
Journal: Neuro-Oncology (2022)

Abstract Adult-onset medulloblastoma is a rare tumor for which limited data exists. Current treatment is based on data from childhood medulloblastoma. We present a retrospective cohort of 130 consecutive patients age ≥ 18 years and treated at the University of Washington (N = 61), University of Florida (N = 50), and Stanford University (N = 19), from 2000-2021. Median duration of follow-up was 57.3 months. Patients were 57.7% male (75/130), with median age at diagnosis of 29 years. 5 and 10-year overall survival were 78.9% and 67.6% and no recurrence was seen beyond 10 years. 31/130 (23.8%) patients had Chang M1 or greater disease and molecular typing was available for 41/130 patients. There was no improvement in progression-free survival (PFS) or overall survival (OS) either in patients who received proton therapy or those who received concurrent vincristine. There was a trend favoring longer OS in patients receiving radiotherapy within 6 weeks of surgery. A trend towards shorter OS in patients receiving a higher craniospinal radiation dose ( &amp;gt; 30Gy) likely reflected accurate clinical risk stratification. There was no improvement in OS or PFS for adjuvant chemotherapy overall, but patients receiving ≥ 5 cycles had improved PFS (HR 2.10, 95% CI = 1.19 - 3.90, p = 0.038) and a trend to improved OS (HR 2.07, 95%CI = 0.81-5.25, p = 0.125). After first progression, median OS was 20.7 months and both 5 and 10-year survival were 24.8%. We conclude that surveillance past 10 years may be unnecessary and that 1 in 4 patients achieve long-term survival after first relapse. Within the confines of a retrospective study, these data suggest equivalence between proton and photon radiotherapy, no benefit to concurrent vincristine, and that at least 5 cycles of adjuvant chemotherapy are required to delay progression.
CTNI-44. A PHASE 0 ‘TRIGGER’ TRIAL OF PAMIPARIB IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA PATIENTS
Authors: Nader Sanai, Yu-Wei Chang, Jun Jiang, Jennifer Molloy, Chelsea Montgomery, Jocelyn Harmon, Amy Hong, John Wanebo, William Kennedy, Michael Garcia, Igor Barani, Wonsuk Yoo, Artak Tovmasyan, An-Chi Tien, Jing Li, Shwetal Mehta
Journal: Neuro-Oncology (2022)

Abstract This study evaluates glioblastoma (GBM) pharmacokinetics (PK) and pharmacodynamics (PD) of pamiparib, a PARP1/2-selective inhibitor, graduating patients to a therapeutic expansion phase of drug plus radiotherapy. Newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID). Tumor tissue cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug &amp;gt; 5-fold biochemical IC50 in nonenhancing tumor determined eligibility for the therapeutic expansion phase. PARP inhibition was assessed via ex vivo radiation and quantification of PAR levels compared to non-radiated control. All patients exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance regimen. In Arms A (n = 20) and B (n = 15), the mean unbound concentrations of pamiparib in Gd-nonenhancing tumor region were 171.5 nM and 102.9 nM, respectively and in Arm C (n = 4) the mean unbound concentration of olaparib was 11.0 nM. All patients in Arms A and B, but only one in Arm C, exceeded the PK threshold to qualify for the expansion phase of the study. 12/20 (60%), 7/14 (50%), and 1/4 (25%) patients in Arms A, B, and C, respectively progressed to expansion phase. Radiation-induced PAR expression was 2.44 fold in untreated control vs 1.16 in Arm A, 0.82 in Arm B and 1.11 in Arm C patients, respectively. The median progression-free survival was 5.4 (Arm A) (n = 7), 5.0 months (Arm B) (n = 6), and 2.7 months (Arm C) (n = 1), respectively. Pamiparib was generally well-tolerated, achieved pharmacologically-relevant concentrations in nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation.
MODL-10. SYSTEMATIC CHARACTERIZATION OF GLIOBLASTOMA GROWTH PATTERNS REVEALS INVASION ROUTE-SPECIFIC FUNCTIONAL SIGNATURES AND DRUG VULNERABILITIES
Authors: Cecilia Krona, Emil Rosén, Soumi Kundu, Karl Holmberg Olausson, Ida Larsson, Ludmila Elfineh, Milena Doroszko, Ramy Elgendy, Johan Wikström, Rebecka Jörnsten, Sven Nelander
Journal: Neuro-Oncology (2022)

Abstract Glioblastomas (GBMs) are malignant brain tumors characterized by uncontrolled, invasive growth along multiple anatomical pathways. GBM is well-studied on a genetic and molecular level, but clinically relevant, experimentally tractable models of invasive growth are largely lacking. We report an integrated study of patient-matched information including clinical and radiological data, patient-derived xenografts, genomics, transcriptomics, epigenomics, and drug response data. Our hypothesis is that joint variation across these levels can expose treatments and biomarkers associated with glioblastoma invasion and recurrence. In total, 64 patient-derived cell lines (PDCLs) were injected into the striatum of n &amp;gt;= 4 mice each, of which 45 PDCLs successfully formed tumors. The tumor-forming PDCLs were each scored with respect to 10 distinct growth characteristics (n= 182 mice). The repertoire of phenotypes was highly divergent and included clear cases of perivascular invasion, white matter invasion, perineuronal satellitosis, and gliosarcoma. We explored if cellular pathways, monitored by RNA sequencing, could account for these differences. DNA repair, Wnt-, and Notch-pathways were predictive of tumor initiation, whereas pathways related to hypoxia, metabolic reprogramming, cellular stress, and inflammation reduced tumor initiation capacity of PDCLs. Transcriptional signatures were also strongly predictive of route-specific invasion. Diffuse invasion was predominantly seen in classical-subtype PDCLs with astrocytic or outer radial glia-like signatures. Proneural PDCLs, in turn, grew as solid tumors with an invasive peripheral region, and mesenchymal tumors were demarcated and invaded around vasculature. To explore the therapeutic implications of our findings, we used our data-driven method TargetTranslator to predict the drug vulnerabilities of different types of invasive glioblastoma. Transcriptional signatures of diffusively growing tumors suggested a vulnerability to neuroactive substrates while perivascular invading tumors would be more susceptible to CDK- and RTK inhibitors. We expect that focusing on drivers of these functional signatures will greatly facilitate the search for effective compounds targeting distinct growth behaviors.
CTNI-07. LOMUSTINE/TEMOZOLOMIDE CHEMOTHERAPY FOR NEWLY DIAGNOSED MGMT-METHYLATED IDHWT GLIOBLASTOMA ACCORDING TO CETEG/NOA-09: REAL-WORLD EXPERIENCE IN A MULTICENTER COHORT
Authors: Johannes Weller, Thomas Zeyen, Uwe Schlegel, Lazaros Lazaridis, Jan-Michael Werner, Julia Onken, Pia Zeiner, Richard Drexler, Peter Hau, Clemens Seidel, Lucia Grosse, Hans Clusmann, Michael Sabel, Florian Ringel, Josef Pichler, Oliver Grauer, Thomas Hundsberger, Oliver Schnell, Maximilian J Mair, Martin Uhl, Friederike Schmidt-Graf, Martin Glas, Norbert Galldiks, Meike Unteroberdörster, Joachim Steinbach, Franz Ricklefs, Mirjam Renovanz, Daniel Ivanov Delev, Merih O Turgut, Oliver R Flesch, Debora Cipriani, Matthias Preusser, Sied Kebir, Martin Misch, Roland Goldbrunner, Manfred Westphal, Ghazaleh Tabatabai, Niklas Schäfer, Matthias Schneider, Hartmut Vatter, Frank Giordano, Christina Schaub, Ulrich Herrlinger
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION The CeTeG/NOA-09 trial demonstrated superior median overall survival (mOS, 48.1 months) in MGMT-methylated glioblastoma treated with lomustine/temozolomide compared to temozolomide. We retrospectively analyzed an off-study cohort of patients treated with lomustine/temozolomide to gather real-world data on this new regimen. METHODS Adult patients from 20 centers in Germany, Austria and Switzerland were included. Inclusion criteria were MGMT-methylated IDHwt glioblastoma newly diagnosed prior to end of 2020, and lomustine/temozolomide treatment as part of first-line therapy. RESULTS 321 patients with a median age of 57 years (range, 21-78) and a median follow-up of 19.9 months were included. In the whole cohort, mOS was 41.0 months (95%CI, 33.0 – not reached). In patients starting lomustine/temozolomide immediately upon initiation of radiotherapy strictly following the CeTeG protocol (88%), mOS was 52.8 months (35.8 – not reached) as compared to 24.6 months (17.6 – not reached) in patients starting lomustine/temozolomide after completion of radiotherapy/concomitant temozolomide (12%, logrank test: p = 0.06). Patients with a KPS &amp;lt; 80 had a shorter mOS of 19.7 months (95%CI, 16.6 – not reached) compared to 41.0 months (33.0 – not reached, p = 0.009) in KPS 80-100. Gross total resection (GTR, 53.9%) was associated with longer mOS (52.8 months, 95%CI 24.1 – not reached) compared to partial resection/biopsy (30.5 months, 95%CI 36.8 – not reached, p=0.004). Multivariable Cox regression analysis confirmed GTR (HR 0.66, p = 0.033) and younger age ( ≤ 50 years: HR 0.42, p = 0.001), but not KPS (80-100 vs. lower: HR 0.66, p = 0.12) as independent prognostic factors. DISCUSSION In this real-world multicenter cohort, survival was similar to the promising results of CeTeG/NOA-09. Further analyses should investigate a potentially reduced benefit from lomustine/temozolomide in patients with low KPS/no GTR and a possible detrimental effect from deferred lomustine/temozolomide initiation. The median follow-up is admittedly short, updated data will be presented.